Centromere conversion and retention in somatic cell hybrids.

The generation of somatic cell hybridization-derived cell lines between highly divergent species affords the opportunity to examine the concept of 'genome dominance' in the context of genetic and epigenetic changes. While whole-scale genome dominance has been well documented in natural hybrids among closely related species, an examination of centromere position and sequence retention in 2 marsupial-eutherian hybrids has revealed a mechanism for 'centromere dominance' as a driving force in the generation of stable somatic cell hybrids following an initial period of genomic instability. While one somatic cell hybrid cell line appeared to retain marsupial centromere sequences which remained competent to recruit the centromere-specific histone variant CENP-A in a Chinese hamster background, fusion events between marsupial and mouse-derived chromosomes in another hybrid line led to a centromere sequence conversion from one species to the other. We postulate that the necessity to maintain an epigenetically defined centromere following genome hybridization may be responsible for retention of specific chromosomes and may result in rapid sequence turnover to facilitate the recruitment of CENP-A containing histones.

A novel palladium-mediated coupling approach to 2,3-disubstituted benzo(b)thiophenes and its application to the synthesis of tubulin binding agents.

[structure: see text]. Flexible, convergent access to 2,3-disubstituted benzo[b]thiophenes has been developed. The most concise approach involves sequential coupling of o-bromoiodobenzenes with benzylmercaptan and zinc acetylides to give benzyl o-ethynylphenyl sulfides which react with iodine to give 3-iodobenzo[b]thiophenes in a 5-endo-dig iodocyclization. These iodides can be further elaborated using palladium-mediated coupling and/or metalation techniques. This method has been applied to the synthesis of some novel tubulin binding agents.

A multi-component coupling approach to benzo[b]furans and indoles.

A single step access to multiply substituted benzo[b]furans and indoles has been developed.

Pharmacologic management of Alzheimer disease, Part I: Hormonal and emerging investigational drug therapies.

OBJECTIVE: To provide information about current genetic research in Alzheimer disease (AD) and potential pharmacologic interventions. Investigational pharmacologic management of AD, including serenics, hormonal therapy, neurotransmitter augmentation, neurobiologic agents, nootropics, and ampakines are also reviewed. DATA SOURCES: Studies, review articles, and editorials identified from MEDLINE searches (from January 1993 to December 1996), and bibliographies of identified articles. STUDY SELECTION: Studies, review articles, and editorials addressing current areas of AD pharmacotherapy research, including hormonal therapy and select investigational agents. DATA EXTRACTION: Pertinent information was selected and the data were synthesized into a review format. DATA SYNTHESIS: AD is a devastating disease characterized by progressive memory loss, cognitive decline, and behavioral disturbances. The behavioral problems associated with AD can present a difficult clinical challenge. Many patients with AD are intolerant of traditional pharmacologic management, including antipsychotics, antidepressants, and anxiolytics. Hormonal agents, including estrogen, medroxyprogesterone, and cyproterone acetate, may be efficacious therapeutic alternatives in the management of sexual behavioral disturbances in men. Research regarding estrogen's role in AD prevention and effect on cognitive function and behavioral symptoms in women with AD are evaluated. Studies evaluating neurotransmitter augmentation and neurobiologic agents in AD are reviewed. CONCLUSIONS: Environmental, genetic, neurobiologic, hormonal, and neurotransmitter influences, and their respective roles in AD pathology, are being investigated. Researchers concur that it is imperative to recognize the correlation of these factors in the etiology of AD to design effective prevention and treatment strategies. Additional studies are essential to elucidate the most efficacious treatments for AD and the attendant behavioral disturbances.

Pharmacologic management of Alzheimer disease part III: nonsteroidal antiinflammatory drugs--emerging protective evidence?

OBJECTIVE: To provide information about research evaluating the role of nonsteroidal antiinflammatory drugs (NSAIDs) in the prevention, or delay in the onset of, Alzheimer disease (AD). DATA SOURCES: Studies, review articles, and editorials identified from MEDLINE searches (January 1990-December 1996) and bibliographies of identified articles. The addendum lists articles from 1996 to June 1999. STUDY SELECTION: Studies, review articles, and editorials addressing NSAIDs and AD pharmacotherapy research. DATA EXTRACTION: Pertinent information was selected and the data synthesized into a review format. DATA SYNTHESIS: AD is a complex disorder and there are numerous factors involved in the process. The pathology of AD is characterized by the development of amyloid plaques and neurofibrillary tangles. In addition, more than 40 immunoprotective proteins that are not unique to AD are found at autopsy that are normally absent, or present in very low concentrations, in normal brain. These findings suggest that AD may involve an inflammatory process. Preliminary results from studies investigating the incidence and onset of AD in patients with arthritis who have taken NSAIDs suggest that NSAIDs may have a protective effect. Studies evaluating the possible association between arthritis, NSAIDs, and AD are reviewed. CONCLUSIONS: Preliminary evidence suggests that NSAIDs may have a protective effect against the development of AD. Further prospective, double-blind, placebo-controlled studies are needed to determine the role of NSAIDs in AD. These dose-finding studies should focus on specific agents and identify the dosage and duration of therapy necessary for a protective or therapeutic effect. Additionally, not all elderly patients are candidates for NSAIDs. Determining the definitive mechanism of action of NSAIDs in AD may suggest alternative agents that have similar pharmacologic activity, but are associated with fewer adverse effects.

Pharmacologic management of Alzheimer disease, Part II: Antioxidants, antihypertensives, and ergoloid derivatives.

OBJECTIVE: To provide information about research evaluating antioxidants in Alzheimer disease (AD) and to discuss the potential role of beta-blockers, angiotensin-converting enzyme inhibitors, clonidine, guanfacine, nimodipine, and ergoloid derivatives in AD therapy. DATA SOURCES: Studies, review articles, and editorials identified from MEDLINE searches (from 1989 to 1997) and bibliographies of identified articles. STUDY SELECTION: Studies and review articles addressing antioxidant, antihypertensive, and ergoloid derivative pharmacotherapy research. DATA EXTRACTION: Pertinent information was selected and the data synthesized into a review format. DATA SYNTHESIS: AD is a progressive neuropsychiatric disorder of unknown etiology. Studies evaluating the possible association between a free radical mechanism in AD and the potential role of antioxidants are reviewed. Additionally, the role of beta-blockers, angiotensin-converting enzyme inhibitors, clonidine, guanfacine, nimodipine, and ergoloid derivatives in AD management are discussed. CONCLUSIONS: Preliminary evidence suggests that antioxidants may have a protective effect against the development of AD. Additional prospective, double-blind, placebo-controlled studies are needed to determine the role of antioxidants in the prevention and management of AD. Understanding the role of antioxidants in AD may suggest alternative agents that have similar pharmacologic activity. Beta-blockers may be an option to control agitation in AD patients for whom anxiolytics or antipsychotics are ineffective or are contraindicated because of their adverse effect profiles. Other agents that may have a role in AD therapy include angiotensin-converting enzyme inhibitors, nimodipine, and ergoloid derivatives. Clonidine and guanfacine have thus far shown little promise in improving cognitive function in AD. Further prospective, double-blind, placebo-controlled trials will be necessary to elucidate the role of these agents in AD management.

Highly functionalized five-membered carbocycles from (3-dialkylamino-1-ethoxyalkenylidene)pentacarbonylchromium complexes and alkynes: the effects of substituents, solvents, ligand additives, and reagent concentrations on the product distribution.

The cocyclization reaction of pentacarbonyl(beta-amino-1-ethoxyalkenylidene)chromium complexes 1 with alkynes has been studied with respect to the effects of substituents, solvents, ligand additives, and reagent concentrations upon the product distribution. This reaction proceeds either as a formal [2 + 2 + 1] cycloaddition to give 5-(1'-dialkylaminoalkylidene)-4-ethoxycyclopent-2-enones 8 or a formal [3 + 2] cycloaddition to give 5-dialkylamino-3-ethoxy-1,3-cyclopentadienes 9. A working hypothesis for the mechanism of this reaction is proposed on the basis of that previously determined for the Dötz reaction. The effects of the aforementioned parameters upon the product distribution of this current reaction are explained in terms of this model. A pronounced ligand-induced allochemical effect has been observed. Conditions for the selective preparation of both classes of cycloadducts 8 and 9 have been determined.

The synthesis and tubulin binding activity of thiophene-based analogues of combretastatin A-4.

A number of analogues of combretastatin A-4 (1), containing a thiophene ring interposed between the two phenyl groups, have been prepared. The synthesis of these compounds employed a combination of palladium-mediated coupling and iodocyclization techniques. The thiophene compounds 11, 14, 18, and 19 also represent non-benzofused analogues of some recently described tubulin binding benzo[b]thiophenes 3-5. The most active thiophene compounds identified in this study were 11, 14, and 18. Overall they are less active than 1 but exhibit comparable activity to the most active of the benzo[b]thiophenes 3-5. A structure-activity relationship of these compounds is considered.